Ann: Positive outcomes in DMD combination therapy animal study, page-113

There is a massive difference between with Antisense is reporting to what the FDA has written on Sarepta's non-clinical studies - this is a concern of mine:

Antisense's view on the quarterly release on the combo Mouse mdx study:

Subsequent to the end of the quarter

To further understand the potential biological mechanisms behind observed functional benefits,
muscle tissue samples have been processed for conducting additional investigations. These
investigations include analysing the levels of dystrophin present in the muscle tissue in the mdx
model (note that mdx mice have no or very low dystrophin levels). An initial analysis of dystrophin
levels was undertaken by MCRI. While dystrophin protein signals were observed in the muscle
tissues of the treated mice, the results were inconclusive as the method used to analyse the
dystrophin levels was insufficiently sensitive, accordingly the muscle tissue is now to be reanalysed to assess dystrophin levels using a more sensitive assay method with the results of this
analysis anticipated in May.

In parallel, plasma samples from the mice have been analysed for a preliminary view of the safety
profile of the combination treatment in this model. While this animal study was not run as a
toxicology study, it is providing helpful insights into the future clinical safety profile of the
combination treatment approach. The Company is prioritising the assessment of markers of
potential liver and kidney toxicity since antisense drugs like ATL1102 and the dystrophin restoration
agents are known to concentrate in these organs. Notably there were no adverse physical changes
(e.g. body weight) or safety ‘signals’ in animals or in the blood markers assessed to date with the
combination treatment.

The MCRI has prioritised its resources towards muscle dystrophin level analysis, accordingly the
work on identifying other potential cellular mechanisms will commence in May. The Company
continues to be highly encouraged by the positive functional benefits observed with the
combination approach and by the prospect of elucidating the underlining biological mechanisms
and will provide updates to the market as new information becomes available.

What is written in the Adcom for Sarepta's AA

Unlike other shortened forms of dystrophin expressed from the endogenous DMD gene, Sarepta’s
micro-dystrophin is expressed from an AAV vector with a MHCK7 promoter and is thus regulated
differently. The biodistribution analysis indicated that the number of vector genomes per nucleus varied
widely across tissues, with the highest quantities of vector DNA present in the liver, followed by the
heart and skeletal muscles. Additionally, there were distinct differences in the micro-dystrophin
expression profile compared to endogenous dystrophin expression, with supraphysiological levels of
micro-dystrophin in the heart, and lower levels in skeletal muscles and liver. The functional
consequences of these differences in the expression profile are unclear.



So, Antisense are saying hard to find, or not found, whereas FDA Adcom/Sarepta are saying easily found.